The major histocompatibility (MHC) class III region includes genes for constituents of the classical (complement C2 and C4) and alternative (complement factor B) pathways of complement activation. The gene for mouse complement C3, another constituent of alternative pathway and the target for both pathways, is syntenic with the MHC on chromosome 17. The structure and expression of genes and gene products of the MHC class III region have been characterized. The wide tissue and cell distribution of complement gene expression suggested novel complement dependent functions. Moreover, insights were revealed regarding the structure/function correlates of complement in well recognized host defenses and immunopathological functions. However, all of these studies were limited in their capacity to assess in vivo significance and/or depended on the discovery of rare complement deficiencies or imperfect models of complement depletion. We have therefore used homologous recombination to develop mouse strains with deletions of factor B and C3. These complement null strains now permit in vivo studies of the importance of the alternative pathway of complement activation in physiological and pathological conditions. This central goal is critical for the development of strategies designed to modulate complement dependent inflammation (e.g., xenograft, ischemic injury, autoimmune disorders) while preserving or enhancing host response to pathogenic microorganisms. Specifically, the proposed studies focus on a determination of the in vivo function of alternative pathway in (a) natural (innate) host defenses, in (b) specific immune functions such as response to specific antigen (including B lymphocyte cell biology), immune clearance and immune mediated tissue injury, and (c) in nonimmune tissue injury. These well defined functions will be studied in mice, a species in which there are background data and capacity to experimentally manipulate immune functions. This provides an ideal setting for elucidating complement dependent mechanisms that will have interesting and important consequences for the control of human disease.